Sustained GnRH peptide-release formulation

ABSTRACT

A pharmaceutical and/or veterinary formulation for sustained release of a peptide agonist or analogue, comprising about 2-15% (w/w) of at least one peptide agonist or analogue other than deslorelin (on an active basis), about 0.5-3.5% (w/w) lecithin and the balance stearin. The formulation preferably comprises a GnRH agonist or analogue and is used for the treatment of various conditions where suppression of sex hormone levels is beneficial, particularly prostate cancer, ovarian and breast cancer, and benign prostatic hyperplasia in dogs.

FIELD OF THE INVENTION

The present invention relates to formulations for the sustained releaseof peptide agonists and analogues. In a particular application of theinvention, the formulation comprises a peptide agonist or analogue ofgonadotropin releasing hormone (GnRH) and is used for the treatment ofprostate and breast cancer and other diseases and conditions wheresuppression of testosterone or estradiol levels is beneficial.

BACKGROUND OF THE INVENTION

The peptide gonadotropin releasing hormone (GnRH) has been the subjectof intensive research for many years. It is a hypothalamic decapeptidewhich is synthesised and stored in neurosecretory cells of the medialbasal hypothalamus. The releasing hormone is released in a pulsatilemanner into the hypophysial portal circulation and is transported to theanterior pituitary. Here, it regulates the secretion of thegonadotrophins, leuteinising hormone (LH) and follicle stimulatinghormone (FSH), into the systemic circulation. Thus, GnRH is a humorallink between the neural and endocrine components of reproductivefunction (for review see Conn PM (ed) 1996 Gonadotropin-releasinghormone Endocrine Review 7:1). GnRH binds to a single class of receptorson gonadotrope cells. Prolonged exposure of these cells to the GnRHresults in loss of responsiveness to the hormone, through receptoralteration (reviewed in Hazum E and Conn PM (1988) Endocrine Review 9:379-866). The outcome of down-regulation of responsiveness to GnRH issuppression of circulating levels of gonadotropins and sex hormones.This has the consequence of suppressing reproductive function and otherprocesses affected by sex hormone levels.

In the present applicant's co-pending International Patent ApplicationNo PCT/AU96/00370 (the disclosure of which is incorporated herein byreference) there is described a formulation comprising deslorelin, aGnRH agonist, as the active agent which, when administered to animals,prevents reproductive function over an extended and predictable periodof time. The formulation also allows the restoration of reproductivefunction following termination of administration. It is also disclosedthat this formulation may be used in the treatment of prostate andbreast cancer and other diseases or conditions where suppression oftestosterone or estradiol levels is beneficial.

The use of GnRH agonists and analogues for the suppression of hormonelevels in humans is well documented. Van Leusden HAIM (GynecolEndocrinol 8 (1994) 215-222) has reviewed the use of a variety of GnRHagonist peptides for suppression of estradiol levels in female patientsand use for the treatment of endometriosis and leiomyoma. From a surveyof a large body of published work, these authors concluded that manyGnRH analogues. including deslorelin, were effective in suppressingestradiol levels and hence in treating these sex hormone-acceleratedconditions provided that the peptide was delivered so as to maintain aconstant minimum blood level. The prerequisite for a peptide to beactive was the ability to disturb the pulsatile release of endogenousGnRH. This required a constant minimum plasma level (this level was notdefined). They suggested that a mode of delivery was more important thanminor differences in potency between different GnRH analogues. Theseauthors also concluded that in a suppressed pituitary, the dose of GnRHanalogue needed to maintain suppression gradually decreased with theduration of treatment (also explored in Sandow J and Donnez T (1990) inBrosens I, Jacobs H S and Rennebaum B (eds) LHRH analogues inGynaecology pp 17-31 Camforth: Parthenon Publishing).

The use of GnRH agonists or analogues for the treatment of variousbenign hormone-dependent diseases and conditions has been described. Forexample, Kappy M, et al. (J. Clin. Endocrinol. Metal. 64 (1987)1320-1322) and Lee P A, et al. (J. Pediatr. 114 (1989) 321-324) describethe long-term treatment of precocious puberty in children using the GnRHagonist, leuprolide acetate. The use of this GnRH agonist in thetreatment of hirsutism (Rittmaster R S & Thompson D L, J. Clin.Endocrinol. Metab. 70 (1990) 1096-1102) and endometriosis (Seltzer V L &Benjamin F, Obstet. Gynecol. 76 (1990) 929) has also been described. Inaddition, GnRH agonists or analogues may be used for treatments ofuterine fibroids (Lumsden M A, et al., Lancet i (1987) 36-37; Healy D L,Gynecol. Endocrinol. 3 (suppl 2) (1989) 33-49), cyclic auditorydysfunction (Andreyko J L & Jaffe R B, Obstet. Gynecol. 74 (1989) 506),porphyria (Bargetzi M J et al., JAMA 261 (1989) 864) and benignprostatic hypertrophy (Gabrilove J L et al., J. Clin. Endocrinol. Metab.69 (1989) 629).

Similarly, the use of GnRH agonists or analogues in the treatment of sexhormone dependent tumours, including breast cancer and prostate cancer,has been described. For example, de Voogt H J et al. (Scand. J. Urol.Nephrol. Suppl. 138 (1991) 131-136) describes the results obtained in aten-year study of prostatic cancer patients administered buserelin, andVogelzang N J et al. (Urology 46 (1995) 220-226) describes the use ofmonthly subcutaneous injections of goserelin in the treatment ofadvanced prostatic cancer. The goserelin was found to be well toleratedand as effective as orchiectomy. Redding et al, (1984) Proc Natl AcadSci USA 81 5845-5848 described the use of a GnRH analogue triptorelinfor suppression of prostate cancer in rats and demonstrated that amicroencapsulated form of the peptide, delivering a controlled dose overa 30 day period was more effective in suppressing serum testosteronelevels and prostate tumour weight than daily subcutaneous administrationof equivalent or double doses of the free peptide. The value of thisanalogue in human prostate cancer patients to suppress testostronelevels and show tumour progression has been demonstrated by Parmar H etal (1985) The Lancet Nov 30, 1201-1205. This one month depot injectionof a GnRH agonist has now been registered for use and tested and usedwidely in the treatment of breast, ovarian and prostate cancer,endometriosis, myoma and in precocious puberty in children, as haveother GnRH agonists (see Nelson J R and Corson S L (1993) Fertil Steril59: 441-3; Paul D et al. (1995) J Clin Endocrin Metab 80: 546-551). Athree month depot preparation of a GnRH agonist has also been described(Okada H et al. (1994) Pharm Res (US) 11: 1199-1203.). Linear drugrelease from the injected microspheres was obtained with persistentsuppression of serum LH, FSH (rats) and testosterone (rats and dogs) forover 16 weeks. Doses of GnRH analogues used to suppress sex hormonelevels in males and females are the same (e.g. Plosker, G L and Brogden,R V (1994) Drugs Vol. 48, pages 930-967). Thus, the demonstration ofsuppression of sex hormone levels in one sex is predictive of similarsuppression in the other sex.

Accordingly, the abovementioned deslorelin formulation developed by thepresent applicant, is also useful for treating a range of hormonedependent diseases and conditions in animals (including humans) such asthose mentioned above. The present applicant has now found that similarformulations including GnRH agonists or analogues other than deslorelincan also be used in treating a range of hormone dependent diseases andconditions in animals, including humans. However, these formulationsoffer an improved treatment for hormone dependent diseases andconditions, by continuing to deliver the GnRH agonist or analogue over aperiod of up to 12 months or more, thus reducing the need for frequentsubcutaneous injections or implant insertions. Whilst formulations forsustained release of bioactive peptides (including GnRH and its agonistsor analogues) for periods of up to 12 months have been previouslyproposed in U.S. Pat. No. 5,039,660, it is to be noted that the onlyrelease results provided in that specification relate to a formulationcomprising GHRH placed in a bath of physiological, buffered saline for aperiod of merely twenty days.

DESCRIPTION OF THE INVENTION

Thus, in a first aspect, the present invention provides a pharmaceuticaland/or veterinary formulation comprising about 2-15%(w/w) of at leastone peptide agonist or analogue other than deslorelin (on an activebasis), about 0.5-3.5%(w/w) lecithin and the balance stearin.

In a preferred embodiment of the present invention. the formulationcomprises about 5-10% (w/w) peptide agonist or analogue other thandeslorelin(on an active basis), about 0.5-1.5% (w/w) lecithin and about89-94% (w/w) stearin.

Preferably, the peptide agonist or analogue is a GnRH agonist oranalogue other than deslorelin. Particularly preferred formulations are;

(I) 94% (w/w) stearin, 5% (w/w) GnRH agonist or analogue other thandeslorelin (on an active basis) and 1% (w/w) lecithin, and

(II) 93% (w/w) stearin, 5% (w/w) GnRH agonist or analogue other thandeslorelin (on an active basis) and 2% (w/w) lecithin.

In a still further preferred embodiment of the present invention theformulation is for administration to an animal selected from dogs, cats,other domestic animals, captive wildlife and humans.

Typically, the formulation of the first aspect will release the peptideagonist or analogue, in vitro, into phosphate buffered saline (PBS: pH7.3, prepared by dissolving 8.00 g of sodium chloride, 1.00 g di-sodiumhydrogen phosphate anhydrous, 0.40 g sodium dihydrogen phosphatedihydrate (0.31 g if anydrous), and 0.05 g sodium azide in 1 litre ofdeionised water), at 37° C. at a rate of about 2-350 μg/day for at least200 days but preferably for at least 300 days.

The excipient(s) of stearin and lecithin is preferably in anon-crystalline form.

The formulation will typically exist in the form of rods which have beenextruded. The rods may be cut into predetermined lengths forimplantation in the animal. As will be readily appreciated, the lengthof rod will determine the rate and dose of the peptide agonist oranalogue. As opposed to implanting longer rods more than one rod can beimplanted in each animal.

Histopathological examinations conducted on dogs have shown,unexpectedly, that implanted rods of the formulation of the first aspectprovoke only a minimal to mild inflammatory response resulting in theencapsulation of the rod or remnants within a thin layer of fibroblasts.While not wishing to be bound by theory, it is believed that the successof the formulation of the first aspect to continue to release thepeptide agonist or analogue over periods of up to 12 months or more isdue, at least in part, to the apparent ability of the formulation to bewell tolerated in the animal body. The provocation of a strongerinflammatory response than that observed, could have been otherwiseexpected to result in the rod or remnants being heavily encapsulated byfibrous tissue thereby stifling release of the peptide agonist oranalogue.

It will be appreciated by persons skilled in the art, that alternativeformulations comprising excipient(s) with similar characteristics tothose included in the formulation of the first aspect may likewiseprovoke minimal to mild inflammatory responses and consequently beuseful for the sustained release of peptide agonists or analogues. Suchalternative formulations are to be regarded as falling within the scopeof the present invention.

In a second aspect, the present invention consists in a method oftreating a disease or condition in an animal, the method comprisingadministering to the animal the formulation of the first aspect of theinvention.

The disease or condition referred to in the method of the second aspectof the invention is, preferably, any disease or condition whereinreduction of sex hormone (testosterone or estradiol) levels over aprolonged period is beneficial. Examples include prostate cancer,ovarian and breast cancer, benign hormone-dependent disorders such asendometriosis, myoma and premenstrual tension, uterine fibroids,hirsutism, cyclic auditory dysfunction, porphyria and precocious pubertyin children.

Persons skilled in the art will be well aware of a variety of GnRHagonists or analogues which can be usefully employed in the presentinvention. Examples of some of the GnRH agonists or analogues which maybe used in the present invention include eulexin (described inFR7923545, WO 86/01105 and PT100899), goserelin (described in U.S. Pat.No. 4,100,274, U.S. Pat. No. 4,128,638, GB9112859 and GB9112825),leuprolide (described in U.S. Pat. Nos. 4,490,291, 3,972,859, 4,008,209,4,005,063, DE2509783 and U.S. Pat. No. 4,992,421), dioxalan derivativessuch as are described in EP 413209, triptorelin (described in U.S. Pat.Nos. 4,010,125, 4,018,726, 4,024,121, EP 364819 and U.S. Pat. No.5,258,492) meterelin (described in EP 23904), buserelin (described inU.S. Pat. Nos. 4,003,884, 4,118,483 and 4,275,001), histrelin (describedin EP217659), nafarelin (described in U.S. Pat. No. 4,234,571,WO93/15722 and EP52510), lutrelin (described in U.S. Pat. No.4,089,946), leuprorelin (described in Plosker et al, Drugs 48 930-967,1994) and LHRH analogues such as are described in EP181236, U.S. Pat.Nos. 4,608,251, 4,656,247, 4,642,332, 4,010,149, 3,992,365 and4,010,149. The disclosures of each the references referred to above areincorporated herein by cross reference.

Preferred GnRH agonists or analogues include goserelin, leuprorelin,triptorelin, meterelin, buserelin, histrelin, nafarelin and combinationsthereof. The formula of these compounds is provided below:

Goserelin C₅₉H₈₄N₁₈O₁₄C₂H₄O₂ D-Ser(Bu^(t))⁶Azgly¹⁰-LHRH Acetate 3-[5oxo-L-prolyl-L-tryptophyl-L-seryl-L-tyrosyl-(3-O-tert-butyl)-D-seryl-L-leucyl-L-arginyl-L-prolyl] cabazamide acetate.Leuprorelin C₅₉H₈₄N₁₆C₁₂, C₂H₄O₂ Leuprorelin Acetate5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate. TriptorelinC₅₉H₈₄N₁₆O₁₂, C₂H₄O₂ D-Trp⁶-LHRH5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L- prolylglycinamide. MeterelinDes Gly¹⁰-2-methyl-D-Trp⁶-Pro-ethyl-amide⁹ LHRH. Buserelin C₆₀H₈₆N₁₆O₁₃,C₂H₄O₂ D-Ser(Bu^(t))⁶-Pro9-NEt LHRH Acetate Oxo-L-prolyl-L-histidylL-tryptophyl-L-seryl-L-tyrosyl-O-tert-butyl-D-seryl-L-leucyl-L-arginyl-N-ethyl-L- prolinamide acetate.Histrelin Pro-His-Trp-Ser-Tyr-Leu-D(N-benzyl) His-Arg-Pro-N- ethylamideNafarelin C₆₆H₈₃N₁₇O₁₃, xC₂H₄O₂yH₂OOxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-N-ethyl-L- prolylglycinamindeacetate hydrate.

Stearin is partially hydrogenated palm oil. Its principle fatty acidsare C16:0(45%) and C18:0(53%). Melting point is about 55° C.

Lecithin is a composition mainly comprised of phosphatidylcholine. It isa mixture of diglycerides of stearic, palmitic and oleic acids linked tothe choline ester of phosphoric acid. Both stearin and lecithin arefound in plants and animals.

In a third aspect, the present invention consists in a method ofpreventing reproductive function in an animal, the method comprisingadministering to the animal the formulation of the first aspect of theinvention.

In addition, the formulation described in PCT/AU96/00370 comprisingdeslorelin as well as other similar formulations comprising other GnRHagonists and analogues, are also well suited for use in the treatment ofbenign prostatic hyperplasia, a condition which is common in dogs butuncommon to rare in other species.

Benign prostatic hyperplasia, which results from androgenic stimulation,is the most common prostatic disorder of dogs and is found in mostintact male dogs aged >6 years old. The most common clinical signs aretenesmus, hematuria, bleeding from the penis and chronic recurrentinfections of the urinary tract. These signs may be accompanied bynonspecific signs including fever, malaise and caudal abdominalpain—often present with bacterial neoplasia. In addition, prostaticdiseases may cause infertility, incontinence or urethral obstruction.

The present treatment of choice for benign prostatic hyperplasia iscastration. Following castration, prostatic involution is usuallyevident within a few weeks and is complete within a few months. Formales intended for breeding, other treatments involving antiandrogensmay be feasible. These drugs inhibit androgen synthesis and counteractthe effect androgens have on spermatogenesis. Their long term use,however, is undesirable since it can lead to sterility.

The present applicant considers that the use of long term GnRH agonisttherapy to desensitise pituitary receptors and hence reduce gonadotrophproduction with a consequent reduction or elimination of androgens, isan adequate alternative to castration and the use of antiandrogens.

Accordingly, in a fourth aspect, the present invention consists in amethod of treating benign prostatic hyperplasia in an animal, the methodcomprising administering to the animal a formulation comprising about2-10%(w/w) of at least one GnRH agonist or analogue (on an activebasis), about 0.5-2.5%(w/w) lecithin and the balance stearin.

In a preferred embodiment of the method of the fourth aspect, theformulation utilised comprises about 5-10% (w/w) GnRH agonist oranalogue (on an active basis), about 0.5-1.5% (w/w) lecithin and about89-94% (w/w) stearin.

The at least one GnRH agonist or analogue is preferably selected fromthe group consisting of deslorelin, goserelin, leuprorelin, triptorelin,meterelin, buserelin, histrelin, nafarelin and combinations thereof. Itis presently preferred that the GnRH agonist or analogue is deslorelin.

Deslorelin is described in U.S. Pat. No. 4,218,439. Deslorelin has theformula [6-D-tryptophan-9-(N-ethyl-L prolinamide)-10-deglycinamide] or PGlutamine-Histidine-Tryptophan-Serine-Tyrosine-DTryptophan-Leucine-Arginine-Proline-ethylamide.

In a still further preferred embodiment of the method of the fourthaspect, the formulation utilised is for administration to dogs, cats,other domestic animals, captive wildlife and/or humans.

Again, the excipient(s) of stearin and lecithin is preferably in anon-crystalline form.

Typically, the formulation utilised in the method of the fourth aspectwill release the GnRH agonist or analogue, in vitro, into phosphatebuffered saline (prepared as described above), at 37° C. at a rate ofabout 2-80 μg/day for at least 200 days but preferably at least 300days.

Examples of methods of producing the formulation for administration asimplants, particularly to dogs, are provided in PCT/AU96/00379. As isdescribed therein a formulation comprising 94% stearin, 5% deslorelin(on an active basis) and 1% lecithin was evaluated in dogs. Thisformulation was produced as follows:

Stearin (supplied as free flowing beads of 1 mm or less in diameter madeby Vandenberg Foods) and lecithin (supplied as a deep brown viscoussyrup from R P Schearer) were hand mixed using a spatula in a smallbeaker. The deslorelin was then added and thoroughly mixed into theexcipients. The mixed material was transferred to the barrel of a ramextruder that has a 1 mm nozzle attached and is equilibrated to 55° C.The ram extrusion pressure is 40 psi. The ram was attached and pressureapplied until the product began to extrude. At this point the pressurewas backed off and the product allowed to reach 55° C. The product wasthen extruded-3 g over a 30 second period. The resulting extrudate wasallowed to cool and then broken up and re-extruded through a 1 mmnozzle. This step was included to ensure uniformity of contentthroughout the matrix. The 1 mm nozzle was then replaced with a 2.3 mmdiameter nozzle. The same product temperature equilibration procedurewas conducted prior to extrusion. The product was then extruded andafter cooling the long rods produced could be sectioned into lengths ofthe required weight.

Whilst this method of production involves extrusions at 55° C.,temperatures below this (e.g. 52° C.) which soften the stearin are alsosuitable.

The rods produced were implanted into male dogs using standardtechniques. Results obtained demonstrated that the release of deslorelinfrom the rods in vitro followed a reproducible path and continued for upto 250 days. In the dogs a continued decline in testicular size was seenfor at least 5 months and suppression of plasma testosterone levels forat least 4 months were observed.

In addition, as is also described in PCT/AU96/00379, a formulationcomprising 93% stearin, 5% deslorelin (on an active basis) and 2%lecithin was evaluated in dogs. This formulation was produced asfollows:

Stearin beads (ADMUL PO 58 from Quest International Australasia Limited)and lecithin (Topcithin 300, Bronson & Jacobs, Australia) were handmixed using a spatula in a small beaker. The deslorelin was then addedand thoroughly mixed into the excipients. The material was transferredto the barrel of a ram extruder that has a 1 mm nozzle attached and isequilibrated to 55.8° C. The ram extrusion pressure is 40 psi. The ramwas then attached and pressure applied until the product began toextrude. At this point the pressure was backed off and the productallowed to reach 55.8° C. The product was then extruded-3 g over a 30second period. The resulting extrudate was allowed to cool and thenbroken up before re-extruding the mixed granulation through the 1 mmnozzle at 58.3° C. and into an injectable mould that generates afinished rod product that is 2.3 mm in diameter and approximately 25 mmlong. The rods are then sterilised by gamma irradiation.

The rods produced were implanted into male and female dogs (0.5, 1 or2×120 mg rod containing 6 mg of deslorelin). The results showed that theformulation is able to suppress testosterone levels in dogs for 12months or more and in bitches for at least 5 months. Accordingly, theformulation of the present invention is able to prevent reproductivefunction in dogs over an extended period of time.

In further experiments, rods containing goserelin, leuprolide, buserelinor triptorelin were produced in the same manner as described aboveexcept that the deslorelin was replaced with the goserelin, leuprolide,buserelin or triptorelin.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in more detail with reference to theaccompanying drawings, in which:

FIG. 1 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(control—0 mg);

FIG. 2 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(deslorelin—3 mg);

FIG. 3 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(deslorelin—6 mg);

FIG. 4 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(deslorelin—12 mg);

FIG. 5 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(goserelin—6 mg);

FIG. 6 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(leuprolide—6 mg);

FIG. 7 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(busereline—6 mg);

FIG. 8 shows the results of implantation into dogs of rods in accordancewith the invention in scrotal circumference monitored over time(triptorelin—6 mg);

FIG. 9 shows the results of monitoring of plasma testosterone levels inthe implanted dogs treated in accordance with Treatment 1 described inFIG. 1 (control—0 mg).

FIG. 10 shows the results of monitoring of plasma testosterone levels inthe implanted dogs treated in accordance with Treatment 2 described inFIG. 2 (deslorelin—3 mg).

FIG. 11 shows the results of monitoring of plasma testosterone levels inthe implanted dogs treated in accordance with Treatment 3 described inFIG. 3 (deslorelin—6 mg).

FIG. 12 shows the results of monitoring of plasma testosterone levels inthe implanted dogs treated in accordance with Treatment 4 described inFIG. 4 (deslorelin—12 mg).

FIG. 13 shows the results of monitoring of plasma testosterone levels inthe implanted dogs treated in accordance with Treatment 5 described inFIG. 5 (goserelin—6 mg).

FIG. 14 shows the results of monitoring of plasma testosterone levels inthe implanted dogs treated in accordance with Treatment 6 described inFIG. 6 (leuprolide—6 mg).

EXAMPLE

Effect of rod implants comprising GnRH agonists on scrotal circumferenceand plasma testosterone levels.

Rods in accordance with the invention were implanted into dogs andchange in scrotal circumference (which is closely related with testiclesize and plasma testosterone levels) monitored over time. The resultsobtained are shown in the accompanying FIGS. 1 to 8 in which:

Treatment 1 Control (0 mg) (FIG. 1) Treatment 2 Deslorelin 3 mg (FIG. 2)Treatment 3 Deslorelin 6 mg (FIG. 3) Treatment 4 Deslorelin 12 mg (FIG.4) Treatment 5 Goserelin 6 mg (FIG. 5) Treatment 6 Leuprolide 6 mg (FIG.6) Treatment 7 Buserelin 6 mg (FIG. 7) Treatment 8 Triptorelin 6 mg(FIG. 8)

The amount (mg) each dog received refers to the amount of the respectiveGnRH agonist implanted in the dog. Each treatment was tested on fivedogs.

Plasma testosterone levels were also monitored in the implanted dogstreated in accordance with Treatments 1 to 6. The results are shown inthe accompanying FIGS. 9 to 14.

Histopathological examination conducted on some of the treated dogs atthe site of implant revealed that the rods cause minimal or only mildinflammation. Remnants of the implants were found to be encapsulated bya thin layer of fibroblasts.

Dog 1

Treatment 1—Implant in Place for Approx. 14 Months

Remnants of the implant appeared to be “walled off” from the surroundingsubcutaneous fatty tissue by a thin capsule of fibroblasts with an innerlining of macrophages that appear to be invading the capsule. There wasonly a mild multi-focal lymphoplasmacytic inflammation in the connectivetissue surrounding the encapsulated implant.

Dog 4

Treatment 3—Implant in Place for Approx. 13 Months

Remnants of the implant were present and appeared as amorphouseosinophilic material in the subcutaneous fatty tissue, walled off by athin capsule of fibroblasts. There was no significant inflammationassociated with the encapsulated implant and the subcutaneous fattytissue surrounding the implant appeared normal.

Dog 79

Treatment 3—Implant in Place for Approx. 14 Months

Remnants of the implant appeared to be present in the subcutaneous fattytissue and appeared to be surrounded by a thin capsule of fibroblastsincluding a few inflammatory cells (macrophages). There was nosignificant inflammation and the subcutaneous fatty tissue appeared tobe normal.

Dog 95

Treatment 2—Implant in Place for 25 Days

The implant site located in the subcutaneous fatty tissue containedremnants of an amorphous, acellular inert substance surrounded by alayer (3-4 cells thick) which contained a mixture of mononuclear cells.These findings are consistent with a very mild foreign body reaction.

The term “on an active basis” is to be given its usual meaning in theart. That is, it is used to indicate that the % amount (w/w) of peptideagonist or analogue present in a formulation is based on the dry weightof the peptide agonist or analogue.

The terms “comprise”, “comprises” and “comprising” as used throughoutthe specification are intended to refer to the inclusion of a statedcomponent or feature or group of components or features with or withoutthe inclusion of a further component or feature or group of componentsor features.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

What is claimed is:
 1. A pharmaceutical and/or veterinary solid implantformulation comprising about 2-15% (w/w) of at least one GnRH peptideagonist selected from the group consisting of goserelin, leuprorelin,triptorelin, meterelin, buserelin, histrelin, nafarelin and combinationsthereof (on an active basis), about 0.5-3.5% (w/w) lecithin and thebalance stearin.
 2. A formulation according to claim 1, comprising about5-10% (w/w) of the GnRH agonist (on an active basis), about 0.5-1.5%(w/w) lecithin and about 80-94% (w/w) stearin.
 3. A formulationaccording to claim 2, comprising about 5% (w/w) of the GnRH agonist (onan active basis), 1% (w/w) lecithin and 94%. (w/w) stearin.
 4. Aformulation according to claim 1, comprising about 5% (w/w) of the GnRHagonist (on an active basis) 2% (w/w) lecithin and 93% (w/w) stearin. 5.A method of treating a disease or condition in an animal for whichsuppression of sex hormone levels is beneficial, the method comprisingadministering to the animal an effective amount of the formulation ofclaim
 1. 6. A method according to claim 5, wherein the disease orcondition is selected from the group consist of prostate cancer, ovarianand breast cancer, endometriosis, myoma, pre-menstrual tension, uterinefibroids, hirsutism, cyclic auditory dysfunction, porphyria andprecocious puberty.
 7. A method of preventing reproductive function fromfunctioning in an animal, the method comprising administering to theanimal the formulation of claim
 1. 8. A method of treating benignprostatic hyperplasia in an animal, the method comprising administeringto the animal a solid implant formulation comprising about 2-10% (w/w)GnRH agonist (on an active basis), about 0.5-2.5% (w/w) lecithin and thebalance stearin whereby treating the benign prostatic hyperplsia.
 9. Amethod according to claim 8, comprising administering about 5-10% (w/w)GnRH agonist (on an active basis), about 0.5-1.5% (w/w) lecithin andabout 89-94% (w/w) stearin.
 10. A method according to claim 8, whereinthe animal being treated is a dog.